tbuckley/cabot-search huggingface dataset:
Abstract 3646: Distinct functions of pancreatic stellate cells in PDAC stromal evolution
Authors: M. Kathrina Casapao Onate, Matthew Schleisman, Zheng Xia, Mara H. Sherman
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the United States with a five-year relative survival rate of 10.8%. After surgery, radiation and chemotherapy are the next lines of therapy. However, these treatments have not significantly improved clinical outcomes due in part to its unique and characteristic desmoplasia, which limits treatment efficacy. Cancer-associated fibroblasts (CAFs) have been shown to contribute in PDAC’s stromal reaction in part viasecretion of extracellular matrix (ECM) components and growth factors, suggesting that CAFs are pro-tumorigenic. This understanding led to several CAF ablation preclinical studies; surprisingly, these studies demonstrated tumor-suppressive potential for CAFs, highlighting the functional heterogeneity among CAFs in PDAC. This emphasizes the need for greater developmental understanding of this influential cell population. Lineage tracing via our recently established Fabp4-Cre;Rosa26mTmG mouse model revealed that pancreatic stellate cells (PSCs), thought to be the main cellular origin of PDAC CAFs, contribute to a minor faction of CAFs yet appear to have non-redundant functions to alternatively-derived CAFs. Here we delve further into the specific functions of PSC-derived CAFs via single-cell RNA sequencing of pancreatic stellate cells in healthy and tumor pancreas with our Fabp4-Cre;Rosa26mTmG mouse model. To our surprise, initial scRNA-seq analysis illustrated that quiescent pancreatic stellate cells from healthy tissue appear to be more heterogeneous to PSC-derived CAFs, with quiescent pancreatic stellate cells clustering into three “super clusters” while PSC-derived CAFs clusters into one “super cluster”. Additionally, clusters specific to normal pancreas tissue revealed potential transcripts-of-interest that are anti-tumorigenic. Current efforts seek to analyze stromal evolution with respect to CAF cell of origin in pre-malignant lesions and throughout stepwise tumorigenesis to metastasis. Furthermore, we are investigating the functional significance of potentially anti-tumorigenic factors lost from the PSC compartment upon differentiation to a CAF phenotype during PDAC progression. These findings shed light on the increasingly appreciated heterogeneity of PDAC CAFs, whilst suggesting that PSC-derived CAFs may be specifically targeted as a singular cell population for therapeutic treatment. Importantly, these findings help gain a greater understanding of PDAC disease progression and development in order to better serve patient care. Citation Format: M. Kathrina Casapao Onate, Matthew Schleisman, Zheng Xia, Mara H. Sherman. Distinct functions of pancreatic stellate cells in PDAC stromal evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3646.
Distribution Pattern of the Monoamine Oxidase B Ligand, 18F-THK5351, in the Healthy Brain
Authors: Kenji Ishibashi, Yoshiharu Miura, Tetsuro Tago, Jun Toyohara, Mana Higashihara, Atsushi Iwata, Kenji Ishii
Journal: Clinical Nuclear Medicine (2022)

Background 18 F-THK5351 PET estimates the concentrations of monoamine oxidase B (MAO-B) that are preferentially located in astrocytes and can be used to visualize and quantify ongoing astrogliosis. To study images of astrogliosis in neurological disorders, it is essential to understand the detailed binding sites of 18 F-THK5351 as the MAO-B ligand under normal conditions. In this study, we examined the detailed distribution pattern of 18 F-THK5351 in the healthy brain by comparing 18 F-THK5351 uptake between subjects taking and not taking the MAO-B inhibitor. Methods Ten healthy controls (HCs: 67.4 [SD, 15.1] years) and 4 patients with Parkinson disease taking the MAO-B inhibitor underwent 18 F-THK5351 PET. The uptake ratio index (URI) was defined to quantify 18 F-THK5351 uptake, using the cerebellum as a reference region. The cerebellar URI was set to zero. Results For HCs, regions with URI ≥1 were preferentially observed in the following order: the striatum, globus pallidus, thalamus, hypothalamus, amygdala, periaqueductal gray, substantia nigra, medulla, hippocampus, and pons. The peak URI values in the corresponding regions were 2.93, 2.47, 2.12, 2.04, 1.84, 1.68, 1.67, 1.37, 1.20, and 1.11, respectively. For all patients with Parkinson disease taking the MAO-B inhibitor, the URI values in all these regions were significantly decreased ( Z score &gt;2) and were reduced from 60.4% to 99.9%, compared with HCs. Conclusions This study presented the detailed distribution pattern of 18 F-THK5351 in HCs and suggests that 18 F-THK5351 uptake largely reflects MAO-B concentrations under normal conditions.
Abstract 3175: Methylmalonic acid in TME signaling
Authors: Vivien Low, Zhongchi Li, Ashley Laughney, Wenbing Jin, Noah Dephoure, Valbona Luga, Ethan Earlie, Bobak Parang, Chunjun Guo, Lewis Cantley, John Blenis
Journal: Cancer Research (2022)

Abstract The importance of metabolic reprogramming in cancer has been long demonstrated by the association of systemic metabolic changes, such as aging, diet and exercise, with cancer outcomes. These systemic shifts, combined with local metabolic alterations within the tumor microenvironment (TME), can all cooperate to foster an environment conducive to cancer progression. In cells derived from primary and metastatic patient tumors, we found that mesenchymal-like cells displayed dysregulated propionate metabolism, leading to increased accumulation and secretion of methylmalonic acid (MMA), a novel aging-induced oncometabolite. This tumor cell-secreted MMA, in addition to increased MMA in the serum of elderly individuals, combine to form high local accumulation of MMA in the TME. We discovered that MMA acts on fibroblasts in the TME, activating them to cancer-associated fibroblasts (CAFs). MMA modifies the cargo of CAF-secreted extracellular vesicles (EVs), which function as a messenger to tumor cells, further promoting epithelial-to-mesenchymal transition, drug resistance, and increased metastasis in vivo. Here, we reveal a novel function of MMA in cancer, demonstrating for the first time that tumor-secreted MMA recruits the tumor microenvironment to drive cancer progression and metastatic reprogramming. Citation Format: Vivien Low, Zhongchi Li, Ashley Laughney, Wenbing Jin, Noah Dephoure, Valbona Luga, Ethan Earlie, Bobak Parang, Chunjun Guo, Lewis Cantley, John Blenis. Methylmalonic acid in TME signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3175.
Macrophage–NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension
Authors: Ruaa Al-Qazazi, Patricia D. A. Lima, Sasha Z. Prisco, Francois Potus, Asish Dasgupta, Kuang-Hueih Chen, Lian Tian, Rachel E. T. Bentley, Jeff Mewburn, Ashley Y. Martin, Danchen Wu, Oliver Jones, Donald H. Maurice, Sebastien Bonnet, Steeve Provencher, Kurt W. Prins, Stephen L. Archer
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)-macrophage activation may promote RVF in PAH. Objectives: Evaluating the contribution of the NLRP3 inflammasome in RV macrophages to PAH RVF. Methods: Rats with decompensated RV hypertrophy (monocrotaline [MCT] and Sugen-5416 hypoxia [SuHx]) were compared with compensated RV hypertrophy rats (pulmonary artery banding). Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptides, and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and in vitro strategies. MCT rats were treated with SC-144 (a GP130 antagonist) or MCC950 (an NLRP3 inhibitor). Macrophage–NLRP3 activity was evaluated in patients with PAH RVF. Measurements and Main Results: Macrophages, fibrosis, and atrial natriuretic peptides were increased in MCT and SuHx RVs but not in left ventricles or pulmonary artery banding rats. Although MCT RV macrophages were inflammatory, lung macrophages were antiinflammatory. CCR2+ macrophages (monocyte-derived) were increased in MCT and SuHx RVs and highly expressed NLRP3. The macrophage–NLRP3 pathway was upregulated in patients with PAH with decompensated RVs. Cultured MCT monocytes showed NLRP3 activation, and in coculture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. In vivo, MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV macrophages and NLRP3 content, prevented STAT3 (signal transducer and activator of transcription 3) activation, and improved RV function without regressing pulmonary vascular disease. Conclusions: NLRP3–macrophage activation occurs in the decompensated RV in preclinical PAH models and patients with PAH. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH RVF results from RV inflammation rather than solely from elevated RV afterload suggests a new therapeutic paradigm.
Abstract 2302: The pan-cancer regulator of the mutant TERT promoter and a new model of the GABP-TERT axis
Authors: Nicholas O. Stevers, Carter Barger, Olivia Lenzo, Chibo Hong, Katarzyna Soczek, Samuel H. Wu, Andrew M. McKinney, Abigail Suwala, Jennifer A. Doudna, Joseph F. Costello
Journal: Cancer Research (2022)

Abstract Ninety percent of human tumors reactivate telomerase reverse transcriptase (TERT) to achieve cellular immortality. The route to immortality found in over 50 cancer types is mutation of the TERT promoter (TERTp) mutations. Studies in glioblastoma have shown the two most common TERTp mutations, G228A and G250A, reactivate TERT expression through de novo E26 transformation specific (ETS) site generation that, in tandem with a native TERTp ETS site, recruits the tetrameric GA-binding protein (GABP) complex formed by two GABP alpha (GABPA) subunits and two tetramer specific GABPB1 (B1) subunits, GABPB1L (B1L). While ten additional TERTp mutations have been described across cancer types, functional studies have been limited to select mutations and cancer types. We found that each de novo ETS motif generating TERTp mutation increases TERTp transcriptional activity in a GABP-dependent manner. Furthermore, our pan-cancer analysis demonstrated selective enrichment of GABPA at the mutant TERTp across 14 cancer types and further determined that this recruitment is necessary for TERT expression. Prior investigations found that CRISPR-cas9 mediated mutagenesis of the B1 ninth exon, specific to B1L, reduces TERT transcriptional activity in a TERTp-mutation dependent manner. We explored B1L targeting in the reversal of tumor cell immortality in several cancers. We found that the B1 dimer restricted isoform, GABPB1S (B1S), is consistently and significantly increased following B1L reduction, which we determined to be the consequence of a disengagement of a GABP tetramer mediated negative feedback loop acting on the B1 promoter. Interestingly, this upregulated B1S expression enables GABP dimer binding and activation of the mutant TERTp thereby compensating for B1L loss. Indeed, knockout of B1L and B1S together resulted in a near complete elimination of GABPA TERTp recruitment and a striking reduction in TERT expression, leading to telomere shortening and ultimately resulting in tumor cell death and senescence. This data identifies GABP as the master regulator of the mutant TERTp across cancer type and de novo ETS mutation type and suggests a new model of the GABP-TERT axis involving both the GABP tetramer, and the GABP dimer. Citation Format: Nicholas O. Stevers, Carter Barger, Olivia Lenzo, Chibo Hong, Katarzyna Soczek, Samuel H. Wu, Andrew M. McKinney, Abigail Suwala, Jennifer A. Doudna, Joseph F. Costello. The pan-cancer regulator of the mutant TERT promoter and a new model of the GABP-TERT axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2302.
Abstract 5250: Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the second-line treatment for advanced gastric cancer
Authors: Huifang Lv, Yunduan He, Caiyun Nie, Beibei Chen, Jianzheng Wang, Weifeng Xu, Jing Zhao, Xiaobing Chen, Junling Zhang
Journal: Cancer Research (2022)

Abstract Objective: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is a key enzyme in irinotecan metabolism. However, the relationship between UGT1A1 genotype and the safety and efficacy of irinotecan monotherapy in the treatment of Chinese advanced gastric cancer remains unclear. Methods: A total of 110 patients were enrolled. Intravenous irinotecan was administered every 3 weeks. Irinotecan dose was selected according to the polymorphism of UGT1A1 gene, which was divided into 3 groups: UGT1A1*6 wild-type (GG type): 125mg/m2, d1, d8; UGT1A1*6 mutant heterozygosity (GA type) 100mg/m2, d1, d8; UGT1A1*6 homozygosity mutation (AA type) 75mg/m2, d1, d8 or paclitaxel 125mg/m2, d1, d8. UGT1A1 genotypes were determined by direct sequencing or next-generation sequencing of genomic DNA extracted from peripheral blood. Results: Among 110 patients of the subjects, the genotypes of UGT1A1*28 were wild-type in 78 patients (70.91%), mutant heterozygosity in 28 (25.45%) and mutant homozygosity in 4 (3.64%). UGT1A1*6 were GG in 67 cases (60.91%), GA in 35 cases (31.82%), and AA in 8 cases (7.27%). There were two heterozygous mutations in 3 patients, and no homozygous mutation was detected. A total of 10 cycles of irinotecan were administered, with a median of five cycles per patient. There was no significant difference in the risk of delayed diarrhea and granulocytopenia in patients with different UGT1A1*28 genotypes (P&amp;gt;0.05), while there was significant difference in the risk of delayed diarrhea and granulocytopenia in patients with different UGT1A1*6 genotypes (P&amp;lt;0.05). The dose intensity of irinotecan was different in patients with different subtypes of UGT1A1*6 gene, and the dose intensity of heterozygous mutant patients was lower than that of wild-type patients. However, there were no significant differences in PFS and OS among patients with different subtypes after dose adjustment and program adjustment (P&amp;gt;0.05). Conclusion: UGT1A1*6 gene polymorphism was significantly associated with diarrhea and neutropenia induced by irinotecan. The safety and effectiveness of antitumor therapy might be significantly improved by individualized drug administration according to the results of UGT1A1*6 gene polymorphism. Citation Format: Huifang Lv, Yunduan He, Caiyun Nie, Beibei Chen, Jianzheng Wang, Weifeng Xu, Jing Zhao, Xiaobing Chen, Junling Zhang. Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the second-line treatment for advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5250.
Abstract 209: Elucidating the role of NMDA subunit NR2B in non-tumor and tumor-bearing mice
Authors: Jesus Castro, Mariana Gaelzer, Scott Welford
Journal: Cancer Research (2022)

Abstract Therapeutic options for glioblastoma multiforme (GBM), the most common and fatal brain tumor, have been limited over the course of recent decades, leaving radiation as one of the few effective therapies. While advancements in radiation therapy have improved life expectancy and patient outcome, exposure to radiotherapy causes normal tissue toxicity and damage to the central nervous system, resulting in cognitive impairment and negative patient side effects. In the hippocampus, the memory processing center of the brain, radiotherapy-induced elevated glutamate levels lead to over-excitation of N-methyl-D-aspartate receptors (NMDAR) and thus cell death. To investigate the NMDAR, we repurposed a NMDA subtype specific inhibitor (Ifenprodil) and treated non-tumor mice before radiation. We found that Ifenprodil rescues cell death and cognition by inhibiting the NR2B subunit of NMDA receptors and preventing over-excitement-induced excitotoxicity, despite presence of high glutamate levels. In order to relieve glioma patients of the negative side effects of radiotherapies, we aim to further investigate the critical role of NR2B inhibition in non-tumor and tumor-bearing mice to reduce excitotoxicity and prevent damage to the central nervous system, opening avenues for therapeutic targeting and drug development. To accomplish this, we designed promotor-specific plasmids, only activated when present in their designed neuronal cell types, to initiate CRISPR/Cas9 genome editing and knock out the NR2B subunit of NMDAR. With NR2B knocked out across 5 different cell types, we exposed hippocampal organotypic slice cultures, derived from non-tumor mice, to 2 Gy radiation and ran flow cytometry to reveal which neuronal NR2B subunits play critical roles in excitotoxic phenotypes. To further these findings, we utilized a recently developed in-utero-electroporation mouse model that produces glioblastomas in immunocompetent mice by inactivating select tumor-suppressor genes via CRISPR/Cas9 genome editing at embryonic day 14.5. By applying different CRISPR/Cas9 gRNAs into our tumor-bearing mice, we can not only explore the robust role of NR2B inhibition in tumor brains with varying expressions, but also shed light onto how NR2B inhibition protects normal brain while leaving tumors radiosensitive. In conclusion, this work seeks to further develop our understanding of radiotherapy-induced cytotoxicity in order to prevent cognitive impairment and negative side effects in patients, improving their quality of life. Ultimately, the results from our findings will lead to the advancement of targeted drug development and therapeutic options. Citation Format: Jesus Castro, Mariana Gaelzer, Scott Welford. Elucidating the role of NMDA subunit NR2B in non-tumor and tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 209.
Abstract 2936: Multi-omic characterization of transitional cell populations in breast cancer
Authors: Michael D. Iglesia, Reyka G. Jayasinghe, Daniel Cui Zhou, Nadezhda V. Terekhanova, John Herndon, Alla Karpova, Siqi Chen, Nataly Naser Al Deen, Kazuhito Sato, Feng Chen, Deborah J. Veis, Ryan C. Fields, William E. Gillanders, Li Ding
Journal: Cancer Research (2022)

Abstract Breast cancer is a heterogeneous collection of diseases grouped by hormone receptor status or by expression of key subtype-determining genes. Breast cancer subtypes, in particular basal-like breast cancer and the luminal breast cancer subtypes, differ by hormonal receptor status, proliferation, genomic instability and mutational signatures, treatment response, and prognosis. The highly distinct signatures of basal-like and luminal breast cancer suggest that they may have different cells of origin within the breast duct. As part of the Washington University Human Tumor Atlas Network (WU-HTAN) program, we generated multi-omic data for 53 samples from 37 breast cancer tumors and 4 normal adjacent tissues. Genomic subtyping was applied to both bulk and single-nucleus RNA sequencing. Analysis of single-nucleus gene expression and chromatin accessibility in epithelial cells underscores similarities between basal-like breast cancer and luminal progenitor cells within the breast duct, and between luminal breast cancer and mature luminal ductal cells. This study links distinct breast cancer subtypes to normal breast cell populations and suggests distinct cells of origin for these cancer types. Citation Format: Michael D. Iglesia, Reyka G. Jayasinghe, Daniel Cui Zhou, Nadezhda V. Terekhanova, John Herndon, Alla Karpova, Siqi Chen, Nataly Naser Al Deen, Kazuhito Sato, Feng Chen, Deborah J. Veis, Ryan C. Fields, William E. Gillanders, Li Ding. Multi-omic characterization of transitional cell populations in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2936.
Gene therapy targeting protein trafficking regulator MOG1 in mouse models of Brugada syndrome, arrhythmias, and mild cardiomyopathy
Authors: Gang Yu, Susmita Chakrabarti, Miroslava Tischenko, Ai-Lan Chen, Zhijie Wang, Hyosuk Cho, Brent A. French, Sathyamangla V. Naga Prasad, Qiuyun Chen, Qing K. Wang
Journal: Science Translational Medicine (2022)

Brugada syndrome (BrS) is a fatal arrhythmia that causes an estimated 4% of all sudden death in high-incidence areas. SCN5A encodes cardiac sodium channel Na V 1.5 and causes 25 to 30% of BrS cases. Here, we report generation of a knock-in (KI) mouse model of BrS ( Scn5a G1746R/+ ). Heterozygous KI mice recapitulated some of the clinical features of BrS, including an ST segment abnormality (a prominent J wave) on electrocardiograms and development of spontaneous ventricular tachyarrhythmias (VTs), seizures, and sudden death. VTs were caused by shortened cardiac action potential duration and late phase 3 early afterdepolarizations associated with reduced sodium current density ( I Na ) and increased Kcnd3 and Cacna1c expression. We developed a gene therapy using adeno-associated virus serotype 9 (AAV9) vector-mediated MOG1 delivery for up-regulation of MOG1, a chaperone that binds to Na V 1.5 and traffics it to the cell surface. MOG1 was chosen for gene therapy because the large size of the SCN5A coding sequence (6048 base pairs) exceeds the packaging capacity of AAV vectors. AAV9- MOG1 gene therapy increased cell surface expression of Na V 1.5 and ventricular I Na , reversed up-regulation of Kcnd3 and Cacna1c expression, normalized cardiac action potential abnormalities, abolished J waves, and blocked VT in Scn5a G1746R/+ mice. Gene therapy also rescued the phenotypes of cardiac arrhythmias and contractile dysfunction in heterozygous humanized KI mice with SCN5A mutation p.D1275N. Using a small chaperone protein may have broad implications for targeting disease-causing genes exceeding the size capacity of AAV vectors.